Manufacture of new basic esters of 1-aryl-cyclopentane-1-monothiocarboxylic acids



Patented Mar. 18, 1952 MANUFACTURE OF NEW BASIC ESTERS OF 1 -ARYL-CYCLOPENTANE 1 MONOTHIO- CAR-BOXYLIC ACIDS Franz Hafliger, Henry Martin,and Rolf Denss, Basel, Switzerland, assignors to J. R. Geigy A.-G.,Basel, Switzerland No Drawing. Application May 17, 1948, Serial No.

UNITED STATES PATENT OFFICE 27,604. In Switzerland May 23, 1947 9Claims.

2, group is in the B- or position of an ethane, or of a propane chain,the basic amino 'group being either the dimethylamino, diethylamino orpiperidino group may be prepared from cheap and easily availablestarting materials and hence we prefer these compounds. From thetherapeutic standpoint the dimethylamino and diethylamino compounds areparticularly valuable, as are also the non-toxic inorganic and organicR1 salts thereof.

It has been found that the new basic esters 2 7 fi as defined in FormulaI can be obtained by con- R2 l m h l 0 I densing1-aryl-cycloalkyl-l-carboxylic acids of wherein the general Formula II:R1 and R2 each mean a hydrogen atom, a methyl or a methoxy group, 7 nmeans an integer from 2 to 6 inclusive, R1 1cmH2m| OH II means an mtege?at least and or their reactive, functional derivatives, with Am etradlcal of ahphatlc' amino-alcohols of the general Formula IIIcycloahphatic or heterocycllc amine HO CnH2n Am III gz g 'gh g szg i i gggifi g g jggig gfig or their reactive, functional derivatives, wherebywhich are prepared by the methods hereinafter 2 of the two components.be prgsept m u e form of a reactive derivative contaimng a. particularlydescribed and ascertained or by hydrosu1fide or substituted h drosulfidegrou their obvious chemical equivalents. In the above (e g on the onehand as mofmthimcarbox definition of the general formula of the newbasic i a monothimcarbo: no acid ester g esters, the expressionsecondary, heterocyclic th th h d amine signifies heterocyclic compoundscontain- 6 0 61 an as mercap an mg an endocyclic NH gr0uD such as e Thusa l-aryl-cyclopentane-l-carboiryhc acid piperidme or morph01me of thegeneral Formula II, or a reactive func- The invention also includes themethods of tlmtal denvatnfe thereof be reacted Wlth making suchcompounds hereinafter described. baslcany slfbstltuted merCapLa-n 0f thegeneral The invention is more particularly concerned Formula with thecyclopentane compounds, i. e. those of HSC11Hzn-Am IV g g P EP I i m tor with a metallic salt of the same, or, on the 9 of h mven Ion 1s 0provlde other hand, a monothiocarboxylic acid of the new compositionsWhlCh have been found to GeneralFormulaV: possess desirable therapeuticproperties. Broadly speaking the compounds according tothe invn- 40 tionare valuable spasmolytics. More particu- --o-o la-rly, from thetherapeutic standpoint, the new R V compounds are found to beadvantageous for producing effects on the nervous System and its estersor its salts may be reacted with a comsimultaneously on the muscleapparatus ofthe pound of the generalFormula VI: smooth-muscles as wellas of the striatedmuscles. They influence certain functions of thecentral X CnHzn Am VI nervous system. Hence they are particularlywherein X means a halogen atom, a hydroxylsuitable as such or insolution or in other comor ahydrosulphide group. positions-in medicinalremedies for the treatment For purposes of illustration without howeverof diseases of the nervous apparatus or of the limiting the scope of theinvention to this muscle apparatus deriving from trouble in theenumeration the following may be mentioned as nervous system. a few ofthe many such reactions possible.

Those. com-pounds possessing an unsubstituted The, acid chloride of acarboxylic acid of the phenyl radical and in which the basic amino 56general. Formula II is treated with an aminosubstituted mercaptan of thegeneral Formula IV. In place of the acid chloride, another acid halide,the anhydride or the free acid (in the latter case an esterificationcatalyst can be added with advantage) may be allowed to react with themercaptan. Instead of the free mercaptan, its metallic salts may also beemployed.

A preferable method of carrying out the process is to bring thel-aryl-cyclopentane-1-carboxylic acid-chloride and an equimolecularamount of the basic mercaptan together, either in the presence or theabsence of inert organic solvents, such as ether, benzene, dioxane oracetone. The reaction takes place at room temperature, but more rapidlyat higher temperatures. the new bases directly.

Furthermore, esters of carboxylic acids of the general Formula IIespecially phenyl esters undergo alcoholysis (ester-exchange) on heatingwith basically substituted mercaptans of the general Formula IV mostsuitably in the presence of catalysts, such as, for example, thecorresponding sodium mercaptides.

1 aryl cyclopentane 1 monothio carboxylic acids (V) and their saltsreact with halogen-substituted alkylamines of the general Formula VII toyield, again, esters of the general Formula I. The same esters can alsobe obtained by esterifying 1 aryl cyclopentane -1- monothiocarboxylicacid with amino alcohols of the general Formula III and by alcoholysis(esterexchange) of 1-aryl-cyclopentane-1-monothiocarboxylic-alkylor arylesters with aminoalcohols of the general Formula III.

Another process makes use of the reaction between reactive esters, suchas, for example, the hydrochloric-, sulphuricor arylsulphonic acidesters of 1 arylcyclopentane 1 monothiocarboxylicacid-hydroxy-alkyl-esters of the general Formula VIII:

wherein Z means the group obtained on esterifying a hydroxyl group withhydrochloric-, sulphuric-, arylsulphonicor similar acids, and secondaryamines, of the general formula HAm. When tertiary amines are usedinstead of secondary in this process, the quaternary salts of the basicesters having the general Formula I are obtained.

The esters of general Formula VHI required as starting materials forthis process can be prepared, for example, by reacting salts ofl-arylcyclopentane-l-monothio-carboxylic acids with compounds of thegeneral formula:

I The new esters as defined in the general Formula This method yieldsthe hydrochloride ofv substituted compounds, 1 (3 ,4 -dimethyl-phenyl)-cyclopentane-l-monothiocarboxylic acid and its isomers, 1-(2-anisyl)-cyclopentane-l-monothiocarboxylic acid as well as the corresponding 3'-and 4-substituted acids, 1-(3',4'-dimethoxyphenyl) cyclopentane 1monothio-carboxylic acid, 1-(3'-methyl 4'-methoxy-phenyl)cyclopentane-l-monothiocarboxylic acid and similar compounds.

The followin may be cited as examples of secondary aliphatic,cycloaliphatic and heterocyclic amines of the general Formula I-I-Am:Dimethyl-, diethyl-, dipropyl-, di-isopropylamine, di-allylamine,methyl-ethylamine, cyclopentyl-ethylamine, cyclohexyl-methylamine,piperidine, pyrrolidine, morpholine and similar compounds.

By CnH2nis meant a bivalent, aliphatic hydrocarbon residue, e. g.,-CH2CH2-;

C'H2CH2-CH2- -CH2CH2CH2CH2CH2CH2- --CH2-CH-- The following examplesfurther expound and explain the invention, without however limiting thescope of the invention to these particular examples. Parts are given by.weight andtemperatures are in degrees centigrade. The melting pointsare corrected:

Example 1 l-phenyl-cyclopentane -1-monothio-carboxylicacid-,B-diethyl-amino-ethylester-hydrochloride 20.85 parts ofphenylcyclopentane-carboxylic acid-chloride dissolved in parts ofabsolute benzene are added dropwise while stirring to a solution of 26.6parts of B-diethylamino-ethyl mercaptan in 120 'parts of absolutebenzene, whereby the temperature rises to 30-40. After boiling for a fewminutes under reflux, followed by cooling with ice, the precipitateis-filtered off under suction and washed with absolute benzene. Thelumped benzene solutions arewashed with water, dried and the benzeneevaporated off. The residue boils at 122-123 at 005mm. pressure and. isthe required base. 4

To prepare the hydrochloride, the base is dissolved in absolute etherandtreated with'the equivalent quantity of hydrogen chloride dissolved inether; The salt which precipitat'esout is separated by filtration undersuction. After re-crystallisation from acetic ester-methanol it melts at138-140. i This base also gives water-soluble salts with sulphuric-,phosphoric-, acetic-, citric-j. and maleic acids." h

By heating the base with excessethyl bromide the quaternary salt may beobtained inthe form of colourless crystalsywhich readilyfdissolve inwater. and show a M. fPIbf -1'Z6f.

The salt with ethane-are-disulfonic acid has a M. P. of 124-125.

Example 2 ylic acid e-diethylamino-ethylester-hydrochloride CH2 CH2SCHCHN .HCl 3112- Hz 02H!) 22.25 parts of l-(p-tolyl)-cyclopentane-1-carboxylic acid-chloride dissolved in 25 parts ofabsolute benzene are added, while cooling with ice,

to a solution of 19.0 parts of B-diethylaminoethyl-mercaptan in absolutebenzene. After the mixture has been allowed to stand for several hours,aqueous caustic soda is added, and

an ether extract made. The ether-benzene solution is washed with waterand dried. After the solvent has been distilled off, the productremaining, which boils at 140142 under 0.12 mm.

pressure, is the required base. The hydrochloride of this base, preparedby the process described in Example 1, melts at 190-192.

The following compounds, for example, can be prepared by the proceduredescribed in Example 2: 1-(3',4' dimethylphenyl) cyclopentane 1-monothio carboxylic acid-B-diethyl-amino-eth- Boiling point of the base:151-156 at 0.55 mm. pressure. Melting point of the hydrochloride:167-168.

1-(4'-methoxyphenyl) -cyclopentane l-monothio-carboxylicacid-fi-diethylamino-ethylester C CH1 S-CHz-CH;.N

CH?- H2 2Hs Boiling point of the base: Mil-147 at 0.02 mm.

pressure. Melting point of the hydrochloride: 176-178". Further:

o 01:00-45 CHE-om (3H2 \CH2\SCH2CH2-N/ /CH2 CHz-CE2 CH2CH2 o CH3-C 7OC/CH3 CH3 c112 CH2 SCHz CH2N/ 5111b- H2 H3 CH3 0 C% WHPCHZ 7 CH2 CH2Sfi(CH2)4N /OH2 our? B. CHzCH2 B. P. 0.12 l69- 171. Hydrochloride M. P.155-157.

C z CH2 S-(CH2)3-N Hz- H2 C2H5 B. P. 0.1 169-170. Hydrochloride M. P.135-136".

Example 3 1 phenyl cyclopentane 1 monothio carboxylicacid-'y-diethylamino propylester-hydrochloride.

20.85 parts of 1 -pheny1- cyclopentane-l-carboxylic acid-chloridedissolved in parts of absolute benzene are added dropwise to a solutionof 14.7 parts of 'y-diethyl-amino-propyh mercapt'an in 100 parts ofabsolute benzene. A rise in temperature to 30-40 occurs. action mixtureis stirred for some time, then the OZHB benzene is distilled 011 and theresidue recrystal- 1 phenyl cyclopentane' l monothio-carboxylicacid-B-dimethylamino-ethylester hydrochloride A solution of 20.85 partsof l-phenyl-cyclopentane-l-carboxylic acid-chloride in parts of absolutebenzene is added dropwise, while stirring, to 10.5 parts ofB-dimethylamino-ethylmercaptan dissolved in 150 parts of absolutebenzene. The reaction mixture is then heated to boiling for 10 minutes,cooled and filtered under suction. The melting point of thehydrochloride of l-phenyl-cyclopentane-l-monothio-carboxylicacid-B-dimethylamino-ethylester so obtained is 166-167".

Example 5 1 phenyl cyclopentane 1 monothio-carboxylic acid-B-piperidinoethylester-hydrochloride 20.6 parts ofl-phenyl-cyclopentane-l-monothio-carboxylic acid (obtained by the actionof hydrogen sulphide on phenyl-cyclopentane-carboxylic acid chloride inpyridinemelting point 116-117 after recrystallisation from acetone) areboiled for 18 hours with 16 parts of B-piperidinoethyl-chloride and '20parts of potassium car- The rethen the following esters are obtained byemploying the same procedure:

oer-or g (3112 CH: SCH2CH2-N/ /0 CH3 om cnrcng orig-on.

CH2 CH2 S-CHz-CI-lz-CHz-CEh-N Hr- H2 Hydrochloride M. P.: 125-126.

on, CH2 s-oHronQ-oHrcHFoH oHr-N orig- H1 Hydrochloride M. P.: 116-118".

o (;C can. 0%. CHz SCHrCH N Hr z CzHa Hydrochloride M. P.: 147-148.

The procedures detailed in the above examples are capable ofmodification in many respects. Thus, other inert solvents may be used,e. g, ether, dioxane, petroleum distillates or other hydrocarbons.Furthermore, concentrations, reaction-temperatures and reaction-timesmay be varied within certain limits.

Example 6 1-phenyl-cyclopentane-l-thiocarboxylic acid- 26.6 parts ofl-phenyl-cyclopentane-l-carboxylic acid-phenyl ester are heated, whileexcluding moisture, with 4.6 parts of metallic sodium and 73.5 parts ofdry 'y-diethyl-amino-propylmercaptan for 2 hours in the oil-bath at120-130 (oil-bath temperature). The excess'y-diethylamino-propyl-mercaptan is then distilled 011 in vacuo(produced by a water-jet pump) and the residue, after cooling, taken upin ether. The ethereal solution is washed with water and extracted withdilute hydrochloric acid. The base is set free from the combinedhydrochloric acid extracts with 10% caustic soda solution, taken up inether and the ethereal solution dried with sodium sulfate. After theether has been dis-- tilled off on the water-bath l-phenyl-cyclopentane-l-thiocarboxylic acid 'y diethyl aminopropyl-ester remains. Itboils at 136-139 under 0.12 mm. pressure. The hydrochloride, which isprepared as in Example .1, melts at 137-138 8 after recrystallisationfrom acetic ester and methanol.

What we claim is: 1. Process for the manufacture of compounds suitableas medicinal remedies, comprising bringing into contact an acid chlorideof the formula wherein Ar represents a mononuclear aromatic hydrocarbonradical with the equimolecular proportion of a basic mercaptan of theformula HSCnH2n-Am wherein Am represents the radical of a secondaryamine containing from 2 to 5 carbon atoms selected from the groupconsisting of dialkylamino, piperidino, pyrrolidino and morpholinoradicals and n represents an integer from 2 to 6, and separating thehydrochloride ofthe resulting base by filtration.

2. A medicinal remedy comprising essentially GET-CH2 on? om-om acompound selected from the group consisting of the compounds of theformula 0 AI";CC\

CH CH2 S CdIgm-Alll JJH2 Hg wherein Ar represents a mononuclear aromatichydrocarbon radical, Am represents the radical of a secondary aminecontaining from 2 to 5 carbon atoms selected from the group consistingof dialkylamino, piperidino, pyrrolidino and morpholino radicals and nrepresents an integer from 2 to 6, and their water soluble salts.

3. A medicinal remedy comprising essentially a compound of the groupconsisting of 4. A medicinal remedy comprising essentially a compound ofthe formula wherein R represents a straight chain aliphatic hydrocarbonradical containing 2 to .3 carbon atoms, R represents a member selectedfrom the group consisting of methyl and ethyl radicals.

5. A medicinal remedy comprising essentially a water soluble salt of acompound of the formula wherein R represents a straight chain aliphatichydrocarbon radical containing 2 to 3'carbon 9 atoms, R represents amember selected from the group consisting of methyl and ethyl radicals.

6. A medicinal remedy comprising essentially a compound selected fromthe group consisting of and its hydrochloride.

7. A medicinal remedy comprising essentially a compound selected fromthe group consisting of and its hydrochloride.

8. A medicinal remedy comprising essentially a compound selected fromthe group consisting of and its hydrochloride.

9. A medicinal remedy comprising essentially a compound selected fromthe group consisting o1 unwell.

and its hydrochloride.

FRANZ HAFLIGER. HENRY MARTIN. ROLlE DENSS.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS OTHER REFERENCES Hansen et al.: Jour. Am. Chem.soc, vol. (1933), pp. 2872-74.

Clinton et al.: Jour. Am. Chem. $00., vol. 68 (1946), pp. 207677.

1. PROCESS FOR THE MANUFACTURE OF COMPOUNDS SUITABLE AS MEDICINALREMEDIES, COMPRISING BRINGING INTO CONTACT AN ACID CHLORIDE OF THEFORMULA